4-isopropyl-7-methoxy-2a1-methyl-2,2a,2a1,3,5a,9b-hexahydrofluorene[9,1-bc]furan-8-ol, having antitumor activity

FIELD: biotechnology.

SUBSTANCE: invention relates to a novel compound, namely 2,2a,2a',3,5a,9b-hexahydrofluorene[9,1-bc]furan-8-ol of the formula 1 .

EFFECT: enhancement of antitumor activity.

2 dwg, 5 tbl, 1 ex

 

The invention relates to the field of chemistry and medicine, specifically to a new 4-isopropyl-7-methoxy-2a1-methyl-2,2 a,2a1,3,5 a,9b-hexahydrofuro[9,1-bc]furan-8-Olu General formula 1 (including its spatial isomers, including optically active form):

with antitumor activity.

Chemical treatment of cancer is one of the main problems of modern medicine, that's because of lack of effectiveness of many drugs, and related to use of side effects. In addition, tumor cells that survived chemotherapy, often exhibit resistance to a wide range of drugs. Thus, the search for medicines new structural types remains an important and urgent task.

Many anticancer tools used in chemotherapy, are natural compounds, their derivatives or analogues due to the high activity and moderate side effects (G. M. Cragg, P. G. Grothaus, D. J. Newman. Impact of Natural Products on Developing New Anti-Cancer Agents. Chem. Rev., 2009, 109, 3012-3043) [1], (D. G. I. Kingston. Tubulin-Interactive Natural Products as Anticancer Agents. J. Nat. Prod., 2009, 72, 507-515) [2]. A major problem is the low availability of many of these compounds usually are minor metabolites of plant or animal produced the following or their derivatives.

Object of the invention is the creation of new effective agents that have anti-tumor activity, which can be synthesized from available monoterpenoids.

The problem is solved 4-isopropyl-7-methoxy-2a1-methyl-2,2 a,2a1,3,5 a,9b-hexahydrofuro[9,1-bc]furan-8-I of General formula 1,

including its spatial isomers, including optically active forms.

Connection 1 has not been previously described in the literature, it can be synthesized in accordance with scheme 1 the interaction of 4-hydroxymethyl-2 Karen 2 isovanillin in the presence of an acid catalyst, preferably montmorillonite clay. Connection 2, in turn, can be synthesized from 3-carene, one of the main components of turpentine, interaction with formaldehyde and subsequent saponification of the resulting ester by known methods (G. Ohloff, H. Farnow, W. Philipp Zur Kenntnis homologer Alkohole der Terpen ' - und Sesquiterpenreihe X. Synthese Des (+)-3-Hydroxymethyl-Δ4-Carens. Justus Liebigs Ann. Chem., 1958, 613 43-55) [3]. Thus, compound 1 can be obtained in three stages from a common monoterpene 3-carene, using available and inexpensive reagents.

It was investigated the effect of the claimed compounds 1 on the viability of different tumor is human cells. In the result, it was shown that the claimed compound 1 exhibits a high antitumor activity against tumor cell cultures U-937 and MT-4.

Value CD50(the concentration of the compounds in which there is a loss of 50% of the cells) are 50 μm for U-937 and 0.9 µm for MT-4. Connection 1 is moderately toxic to tumor cell culture SEM-13, indicating a high selectivity of its action.

It is shown that the mechanism of antitumor activity of compound 1 is associated with induction of apoptosis in tumor cells monocytes human U-937 (percentage of cells with apoptosis is 24% at 48 hours incubation) and in neoplastic lymphoid cells MT-4 (the percentage of cells with apoptosis is 49% at 72 h of incubation).

The obtained data allow to consider this compound as promising for the creation of medicines in clinical practice.

The invention is illustrated by the following examples:

Example 1. Synthesis of 4-isopropyl-7-methoxy-2al-methyl-2,2 a,2al,3,5 a,9b-hexahydrofuro[9,1-bc]furan-8-ol 1

To a suspension of 0.35 g of K10 clay, calcined for 3 h at 105°C, 4 ml of CH2Cl2sequentially added a solution of 0.120 g of isovanillin (3-hydroxy-4-methoxybenzaldehyde) in 1 ml of CH2Cl2and a solution of 0.100 g of 4-hydroxymethyl-2 Karen 2 in 1 ml of CH2Cl 2. The mixture was stirred for 3 h at room temperature, then added 2 ml of ethyl acetate and 2 ml of acetone, the catalyst was filtered, the solvent was distilled. The residue was divided column chromatography on silica gel. Got 0.075 g (41%) of compound 1.

An NMR spectrum1H (CDCl3), δ, M. D.: 1.96 and 1.97 (2D, J(17, 16)=J(18, 16)=6.7 Hz, 3H, Me(17) and Me(18)); 1.33 (s, 3H, Me(19)); (DD, J(10A, 10E)=16.5 Hz, J(10A, 1)=3.2 Hz, 1H, Ha-C(10)); 2.17 (dddd, J(10E, 10A)=16.5 Hz, J(10th, 1)=5.7 Hz, J(10th, 7)=2.6 Hz, J(10E, 8)=2.0 Hz, 1H, HeFrom(10)); 2.22 (user. septet, J(16, 17(18))=6.7 Hz, 1H, H-C(16)); 2.24 (dddd, J(1, 2)=10 Hz, J(1, 2')=6.7 Hz, J(1, 10E)=5.7 Hz, 1H, H-C(1)); 3.17 (user. DD, J(7, 8)=3.3 Hz, J(7, 10E)=2.6 Hz, 1H, H-C(7)); 3.19 (DD, J(2, 1)=10.0 Hz, J(2, 2')=8.2 Hz, 1H, H-C(2)); 3.76 (DD, J(2', 2)=8.2 Hz, J(2', 1)=6.7 Hz, 1H, N'-C(2)); 3.88 (s, 3H, OMe-C(14)); 4.97 (s, 1H, H-C(4)); 5.62 (sh.S., OH-C(13)); 5.63 (user. DD, J(8, 7)=3.3 Hz, J(8, 10E)=2.0 Hz, 1H, H-C(8)); 6.66 (s, 1H, H-C(12)); 6.89 (s, 1H, H-C(15)).

An NMR spectrum1C (CDCl2), δ, ppm: 45.38 (d, C(1)); 70.93 (t, C(2)); 94.12 (d, C(4)); 132.80 and 138.07 (2 s, C(5) C(6)); 50.09 (d, C(7)); 120.18 (d, C(8)); 140.17 (s, C(9)); at 23.28 (t, C(10)); 50.02 (s, With(11)); 105.02 (d(12)); 145.30 (C, C(13)); 147.93 (s, C(14)); 110.86 (d, C(15)); 34.95 (d, C(16)); 20.72 and 20.90 (2K, (17) and(18)); 26.72 (K, C(19)); 55.89 (K, C(20)).

Example 2.

The effect of compound 1 on the viability of tumor cells T-cell human leukemia MT-4 Cell line MT-4 cells T-cell leukemia, human) were cultured in medium RPMI 1640 containing 10% fetal calf serum, antibiotiki (100 units/ml penicillin and 0.1 mg/ml streptomycin), in an atmosphere of 5% CO2at 37°C.

Cell viability after incubation with compound 1 was determined using the MTT test, which is based on the ability of living cells to make connections on the basis of tetrazole (MTT) in brightly colored crystals formazan that allows spectrophotometric estimate the number of living cells in the preparation. For this, cells were planted in 96-well plates (100 μl of cells with a concentration of 500 thousand cells/ml). Then the cells were added to a solution of compound 1 in DMSO to a final concentration in the medium from 0.1 to 100 µg/ml Cells were incubated in the presence of compound 1 for 3 days under the same conditions. At the end of incubation, without changing the environment to the cells was added a solution of MTT (5 mg/ml) in phosphate-buffered saline to a concentration of 0.5 mg/ml and incubated for 3 h in the same conditions. The medium was removed, cells were added to 100 ál of DMSO, in which the dissolution occurs resulting in the cells of the crystal formazan, and measured the optical density for multi-channel spectrophotometer at wavelengths of 570 and 630 nm, where A570- absorption formosana, and A630- the background of the cell.

Data were represented as the number of live cells relative to control. 100% took the number of cells in the control, where cells were incubated in the absence of a connection, but in the presence of the solvent DMSO.

C is achene CD 50the concentration of compound 1 in which there is a loss of 50% of the cells, as well as CD80and CD90(concentration at which there is death of 80 and 90% of cells, respectively) are shown in table 1. From these data it is seen that the processing cell line MT-4 compound 1 causes 50% mortality at a concentration of compounds 0.9 μm and 80% mortality at a concentration of 96 μm.

Table 1
Cytotoxicity of compounds 1 to neoplastic human cell lines MT-4
CD50, mcmCD80, mcmCD90, mcm
0.996275

Example 3. The effect of compound 1 on the viability of human tumor cells, U-937.

Cell line U-937 (tumor line human monocytes) were cultured in medium RPMI 1640 containing 10% fetal calf serum, antibiotics (100 units/ml penicillin and 0.1 mg/ml streptomycin), in an atmosphere of 5% CO2at 37°C.

Cell viability after incubation with compound 1 was determined using the MTT test, which is based on the ability of living cells to make connections on the basis of tetrazole (M Is T) in brightly colored crystals formazan, that allows spectrophotometric estimate the number of living cells in the preparation. For this, cells were planted in 96-well plates (100 μl of cells with a concentration of 500 thousand cells/ml). Then the cells were added to a solution of compound 1 in DMSO to a final concentration in the medium from 0.1 to 100 µg/ml Cells were incubated in the presence of compound 1 for 3 days under the same conditions. At the end of incubation, without changing the environment to the cells was added a solution of MTT (5 mg/ml) in phosphate-buffered saline to a concentration of 0.5 mg/ml and incubated for 3 h in the same conditions. The medium was removed, cells were added to 100 ál of DMSO, in which the dissolution occurs resulting in the cells of the crystal formazan, and measured the optical density for multi-channel spectrophotometer at wavelengths of 570 and 630 nm, where A570- absorption formosana, and A630- the background of the cell.

Data were represented as the number of live cells relative to control. 100% took the number of cells in the control, where cells were incubated in the absence of a connection, but in the presence of the solvent DMSO.

Value CD50the concentration of compound 1 in which there is a loss of 50% of the cells, as well as CD80and CD90(concentration at which there is death of 80 and 90% of cells, respectively) are shown in table 2. The data show that treatment of cells line the U-937 compound 1 causes 50% mortality at a concentration of compounds 0.9 microns.

Table 2
Cytotoxicity of compounds 1 to neoplastic human cell lines U-937
CD50, mcmCD80, mcmCD90, mcm
50>330>330

Example 4. The effect of compound 1 on the viability of tumor cells T-cell human leukemia CEM-13.

Cell line CEM-13 were cultured in medium RPMI 1640 containing 10% fetal calf serum, antibiotics (100 units/ml penicillin and 0.1 mg/ml streptomycin), in an atmosphere of 5% CO2at 37°C.

Cell viability after incubation with compound 1 was determined using the MTT test, which is based on the ability of living cells to make connections on the basis of tetrazole (MTT) in brightly colored crystals formazan that allows spectrophotometric estimate the number of living cells in the preparation. For this, cells were planted in 96-well plates (100 μl of cells with a concentration of 500 thousand cells/ml). Then the cells were added to a solution of compound 1 in DMSO to a final concentration in the medium from 0.1 to 100 µg/ml Cells were incubated in the presence connected to the I 1 for 3 days under the same conditions. At the end of incubation, without changing the environment to the cells was added a solution of MTT (5 mg/ml) in phosphate-buffered saline to a concentration of 0.5 mg/ml and incubated for 3 h in the same conditions. The medium was removed, cells were added to 100 ál of DMSO, in which the dissolution occurs resulting in the cells of the crystal formazan, and measured the optical density for multi-channel spectrophotometer at wavelengths of 570 and 630 nm, where A570- absorption formosana, and A630- the background of the cell.

Data were represented as the number of live cells relative to control. 100% took the number of cells in the control, where cells were incubated in the absence of a connection, but in the presence of the solvent DMSO.

Value CD50the concentration of compound 1 in which there is a loss of 50% of the cells, as well as CD80and CD90(concentration at which there is death of 80 and 90% of cells, respectively) are shown in table 3. From these data it is seen that the processing cell line CEM-13 compound 1 causes 50% mortality at a concentration of compound 93 microns.

Table 3
Cytotoxicity of compounds 1 to neoplastic human cell lines CEM-13
CD50, mcmCD80/sub> , mcmCD90, mcm
93>330>330

Example 5. The effect of compound 1 on the induction of apoptosis in tumor cells of human U-937.

In the activation of apoptosis is DNA fragmentation due to the activation of endonucleases. To determine the fragmented DNA of cells stained with dye propidium iodide and then determine the percentage of fragmented DNA using flow cytofluorimetry.

Fixed cells in suspension in 70% ethanol by adding 1 ml of cells suspended in phosphate-buffered saline (FSB) (1-5×106cells) to 9 ml of 70% ethanol in a test tube on ice. Next, the cells are centrifuged at 200 g for 3 min, the ethanol is removed, cells are suspended in 10 ml PBS and centrifuged at 300 g for 5 minutes the cells are Then suspended in 0.5 ml PBS and incubated at room temperature for 5 minutes After centrifugation at 300 g for 5 min the precipitated cells are suspended in 1 ml solution for staining DNA. The solution for staining DNA is prepared as follows: dissolve 200 mg of propidium iodide in 10 ml of the FSB, and then add 10 ál of Triton X-100 and 2 mg RNase. The resulting solution is incubated for 15 min at 70°C. For staining of cells incubated for 30 min at room temperature the tour.

Analysis of the cells is carried out by flow cytometry for flow cytofluorimetry FACS Canto. For excitation of fluorescence using laser (wavelength 488 nm), measuring the fluorescence at a length of 600 nm and the light diffusing. Calculate 10000 cells. The number of cells in which the observed apoptosis corresponds to the area of SubG1. The results are shown in Fig.1 and table 4. Used the concentration of compounds 1, causing the death of 50% of the cells. From these data it is seen that the processing cell line U-937 leads to the induction of apoptosis after 24 hours in 13-15% of the cells, and after 48 hours at 22-25% of the cells. The table shows the data of two independent experiments, each was calculated 10 thousand cells.

Table 4
Induction of apoptosis by compound 1 in the tumor cell line human U-937
Compound (concentration, µm)Time, h% of apoptotic cells (U-937)
Experiment 1Experiment 2
The control (cells without a connection)243,1 a 3.9
4821,6
1 (50)2415,213,9
4822,625,4

Example 6. The effect of compound 1 on the induction of apoptosis in tumor cells of human MT-4.

In the activation of apoptosis is DNA fragmentation due to the activation of endonucleases. To determine the fragmented DNA of cells stained with dye propidium iodide and then determine the percentage fragmentirovannoj DNA, using the flowing cytofluorimetry.

Fixed cells in suspension in 70% ethanol by adding 1 ml of cells suspended in phosphate-buffered saline (FSB) (1-5×106cells) to 9 ml of 70% ethanol in a test tube on ice. Next, the cells are centrifuged at 200 g for 3 min, the ethanol is removed, cells are suspended in 10 ml PBS and centrifuged at 300 g for 5 minutes the cells are Then suspended in 0.5 ml PBS and incubated at room temperature for 5 minutes After centrifugation at 300 g for 5 min the precipitated cells are suspended in 1 ml solution for staining DNA. The solution for staining DNA is prepared as follows: dissolve 200 mg of propidium iodide in 10 ml of the FSB, who then add 10 ál of Triton X-100 and 2 mg RNase. The resulting solution is incubated for 15 min at 70°C. For staining of cells incubated for 30 min at room temperature.

Analysis of the cells is carried out by flow cytometry for flow cytofluorimetry FACS Canto. For excitation of fluorescence using laser (wavelength 488 nm), measuring the fluorescence at a length of 600 nm and the light diffusing. Calculate 10000 cells. The number of cells in which the observed apoptosis corresponds to the area of SubG1. The results are shown in Fig.2 and table 5. From these data it is seen that the processing cell line MT-4 leads to induction of apoptosis after 24 hours in 7-12% of the cells after 48 hours in 16-19% of the cells, and after 72 hours in 47-51% of the cells. The table shows the data of two independent experiments, each was calculated 10 thousand cells.

Table 5
Induction of apoptosis by compound 1 in the tumor cell line human MT-4
Compound (concentration, µm)Time, h% of apoptotic cells (MT-4)
Experiment 1Experiment 1
Control 245,12,3
483,43,5
7254,8
1 (0,9)2412,87,2
4819,616,3
7251,247,4

Sources of information

1. G. M. Cragg, P. G. Grothaus, D. J. Newman. Impact of Natural Products on Developing New Anti-Cancer Agents. Chem. Rev., 2009, 109, 3012-3043.

2. D. G. I. Kingston. Tubulin-Interactive Natural Products as Anticancer Agents. J. Nat. Prod., 2009, 72, 507-515.

3. G. Ohloff, H. Farnow, W. Philipp Zur Kenntnis homologer Alkohole der Terpen ' - und Sesquiterpenreihe X. Synthese Des (+)-3-Hydroxymethyl-Δ4-Carens. Justus Liebigs Ann. Chem., 1958, 613 43-55.

4-Isopropyl-7-methoxy-21-methyl-2,2 a,2al,3,5 a,9b-hexahydrofuro[9,1-bc]furan-8-ol of General formula 1,
with antitumor activity.



 

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FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention concerns Mycobacterium tuberculosis growth inhibitors representing (+) and (-)-enantiomers of derivatives of usnic acid containing a furilidene furanone fragment, namely (10R,4Z)-8,13-dihydroxy-7,10-dimethyl-4-(2-furanylmethylidene)-5,16-dioxatetracyclo[7.7.0.02.6.010.15]hexadeca-1,6,8,12,14-pentaen-3,11-dione 4a and (10S,4Z)-8,13-dihydroxy-7,10-dimethyl-4-(2-furanylmethylidene)-5,16-dioxatetracyclo[7.7.0.02.6.010.15]hexadeca-1,6,8,12,14-pentaen-3,11-dione 4b

EFFECT: inhibitors possess the high antimicrobial activity.

2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formulas I, II, III, IV, V, VIII or to their pharmaceutically acceptable salts, wherein: Z represents , or phenyl; D represents or ; X represents N(R9), O, S, S(=O) or S(O)2; each Y independently represents O or S; G represents or ; the other radical values are described in the patent claim. The invention also refers to pharmaceutical compositions based on the above compounds.

EFFECT: there are prepared new compounds and based compositions which can find application for treating malaria or eliminating or inhibiting the growth of Plasmodium species.

30 cl, 3 tbl, 23 ex

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